High-Dose Weekly Carfilzomib Plus Cyclophosphamide and Dexamethasone in the Treatment of Relapsed Multiple Myeloma

Inclusion Criteria: * Relapsed symptomatic multiple myeloma as per the International Myeloma Working group criteria \[Palumbo 2009\]. * Measurable disease, as defined by one or more of the following (assessed within 21 days prior to registration): * Serum M-protein ≥ 5 g/L (0.5g/dL) * Urine Bence-Jones protein ≥ 200 mg/24 hours * Involved serum free light chain (FLC) measurement ≥ 100 mg/L (10 mg/dL), provided serum FLC ratio is abnormal (abnormal if FLC ratio is \<0.26 or \>1.65) * Biopsy proven plasmacytoma * For IgA patients whose disease can only be reliably measured by serum quantitative immunoglobulin (qIgA) ≥ 750 mg/dL (0.75 g/dL) * Prior treatment with at least one, but no more than three, regimens for multiple myeloma * Documented relapse or progressive disease on or after any regimen (subjects refractory to the most recent line of therapy are eligible except those who are refractory to bortezomib and cyclophosphamide as described in exclusion criteria 1. * Achieved a response to at least one prior regimen (defined as ≥ 25% decrease in M-protein) * Age ≥ 18 years. * Life expectancy ≥ 3 months. * ECOG performance status 0-2. * Laboratory Requirements (must be done within 21 days of registration): * Hematology: * Absolute neutrophil count (ANC) ≥ 1.0 × 10\^9/L * Hemoglobin ≥ 8 g/dL (80 g/L) (subjects may be receiving red blood cell (RBC) transfusions in accordance with institutional guidelines) * Platelet count ≥ 50 × 10\^9/L, independent of platelet transfusions for 7 days. (≥ 30 × 10\^9/L if myeloma involvement in the bone marrow is ≥ 50%) * Biochemistry: * ALT ≤ 3.5 x UNL * Serum direct bilirubin ≤ 2 mg/dL (34 μmol/L) (only required if total bilirubin ≥ 2mg/dL (34μmol/L) * Creatinine clearance (CrCl) ≥ 30 mL/minute (Crockcroft and Gault formula) and not on dialysis. * Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate. * Patients must be accessible for treatment and follow up. Patients registered on this trial must be treated and followed at the participating centre. * In accordance with CRO policy, protocol treatment is to begin within 2 working days of patient registration. * Women/men of childbearing potential must have agreed to use a highly effective contraceptive method. Exclusion Criteria: * Refractory to any proteasome inhibitor therapy (bortezomib, ixazomib, etc.) Refractory disease is defined as failure to respond to the proteasome inhibitor, initial response followed by progression while on a proteasome inhibitor, or relapse within 60 days of stopping proteasome inhibitor therapy. * Prior carfilzomib treatment. * POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) * Waldenström's macroglobulinemia or IgM myeloma * Current or previous Plasma cell leukemia defined as (\> 2.0 × 10\^9/L circulating plasma cells by standard differential) * Chemotherapy or investigational agent within 3 weeks prior to registration or antibody therapy within 6 weeks prior to registration * Radiotherapy to multiple sites within 28 days prior to registration; localized radiotherapy to a single site within 7 days prior to registration * Plasmapheresisis within 14 days of registration. * Pregnant or lactating females. * Major surgery within 21 days prior to registration. * Active, uncontrolled bacterial, fungal, or viral infection. * Concurrent amyloidosis * Known human immunodeficiency virus infection. * Active hepatitis B or C infection. * Myocardial infarction within 4 months prior to registration, NYHA Class III or IV heart failure, uncontrolled angina, history of severe coronary artery disease, severe uncontrolled ventricular arrhythmias, sick sinus syndrome, or electrocardiographic evidence of acute ischemia or grade 3 conduction system abnormalities unless subject has a pacemaker. * Uncontrolled hypertension or uncontrolled diabetes within 14 days prior to registration. * Other malignancy, including MDS, within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, or thyroid cancer; carcinoma in situ of the cervix or breast; prostate cancer of Gleason Score 6 or less with stable prostate-specific antigen levels; or cancer considered cured by surgical resection or unlikely to impact survival during the duration of the study, such as localized transitional cell carcinoma of the bladder or benign tumours of the adrenal or pancreas. * Significant neuropathy (≥ grade 3, or grade 2 with pain) within 14 days prior to registration. * Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib). * Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment. * Ongoing graft-versus-host disease. * Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to registration. * Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.